Most epidemiological studies of breast cancer have focused on investigations of genetic polymorphisms in the genes involved in estrogen and carcinogen metabolism. A number of promising associations have been identified, many of which have yet to be replicated. In this competitive renewal application, we propose to confirm some of the promising associations identified in the initial funding cycle and extend our work to the investigation of other novel genes in estrogen metabolism and several major genes in the pathways of angiogenesis, extracellular matrix remodeling, inflammatory response, and prostaglandin synthesis. These genes are involved in regulating the tumor microenvironment and are likely related to, not only the prognosis, but also the risk of cancers large enough to be detected clinically. The proposed study will use data and biological samples collected from the Shanghai Breast Cancer Study (RO1CA64277). Genetic polymorphisms in approximately 25 candidate genes will initially be evaluated using both genotype- and haplotype-approaches in approximately 1200 cases and 1200 controls recruited from 1996 to 1998. Promising associations identified in the initial phase will be re-evaluated in the second set of subjects (1300 cases and 1300 controls) recruited since 2002 in the parent study. This 2-phase study design will effectively balance both Type I and Type 2 errors and provide credible results towards our understanding of the etiology of breast cancer. Results from this study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer.